In the adult human, normal serum phosphorus levels range from 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol phosphorus/L). (Normal serum levels are typically 50% higher in infants and 30% higher in children due to growth hormone effects.) Hyperphosphatemia is a disease state in which there is an abnormally elevated serum phosphorus (Pi) level in the serum. Significant hyperphosphatemia is considered present when serum phosphorus levels are greater than about 5 mg/dL in adults or 7 mg/dL in children or adolescents. [National Kidney Foundation. Am J Kidney Dis 2003; 42 (Suppl 3):S1-S201.]
The kidney plays a central role in maintaining a condition of phosphorus homeostasis in the body of a subject, wherein the amount of phosphorus absorbed from the gastrointestinal tract approximately equals the amount excreted via the kidney. In addition, cellular release of phosphorus is balanced by uptake in other tissues. Hormonal control is provided by parathyroid hormone.
Since the kidney plays a central role in maintaining phosphorus homeostasis, kidney dysfunction is often accompanied by increased phosphorus retention by the body. In early kidney dysfunction, compensatory physiological responses allow for a continued match between urinary phosphorus excretion and phosphorus absorption from the gastrointestinal (GI) tract, and serum phosphorus levels remain near normal values. With more advanced renal failure, however, elevated serum phosphorus is a predictable co-morbidity.
In patients with chronic kidney disease (CKD), phosphorus retention (as evidenced by abnormally elevated serum phosphorus levels) may contribute to progression of renal failure and is a major factor in the development of secondary hyperparathyroidism, renal osteodystrophy, and soft tissue calcification. [Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. New England J Med 2010; 362: 1312-1324.] Hyperphosphatemia in CKD patients is treated by restriction of phosphorus in the diet and pharmacological means. Serum phosphorus is also reduced during dialysis of end-stage renal disease patients undergoing such treatment.
Phosphorus is present in nearly all foods, and absorption of dietary phosphorus from ingesta in the gastrointestinal (GI) tract is very efficient. Normal daily dietary intake varies from 800-1,500 mg of phosphorus. Typically, 70-90% of dietary phosphorus is absorbed, primarily from the jejunum, duodenum, and proximal ileum of the GI tract, although some absorption continues throughout the remainder of the intestinal tract. A small amount of GI excretion occurs.
The efficient absorption of phosphorus from food and the need to provide a diet sufficient to counter the catabolic state of CKD render dietary restriction insufficient to prevent hyperphosphatemia. Moreover, conventional dialysis fails to reduce levels of phosphorus in the blood, and serum phosphorus levels increase with time. Therefore, prevention of phosphorus absorption with pharmacological means is generally required to prevent or reverse hyperphosphatemia and the morbidities and mortality risks associated with it.
Methods for the prevention and treatment of hyperphosphatemia include the use of compounds or compositions that will bind phosphorus in the gastrointestinal (GI) tract of a subject and prevent its absorption into the systemic circulation. Compounds that bind phosphorus in the GI tract are known as phosphorus (Pi) binders. Today, oral phosphate binders are used in over 90% of patients with kidney failure and/or hyperphosphatemia, at an annual cost of approximately $750 million (U.S. dollars) worldwide.
Phosphorous binding is a chemical reaction between dietary phosphorus and a cation of a binder compound. Chemical reaction results in the formation of insoluble and hence unabsorbable phosphate compounds, adsorption of phosphorus-containing anions on the surface of binder particles, or a combination of both processes.
Metal salts comprise the most clinically important class of phosphorus binders and are ingested to bind dietary phosphate and convert it to insoluble phosphate salts, thus preventing its absorption from the GI tract. Known metal salts with phosphate-binding properties are aluminum hydroxide and aluminum carbonate; calcium acetate, calcium carbonate, calcium citrate, calcium alginate, calcium gluconate, calcium lactate, and calcium sulfate; lanthanum carbonate and lanthanum carbonate hydrates; magnesium carbonate and magnesium hydroxide; as well as complex salts of iron. (Not all of these salts have gained therapeutic importance or been considered safe or efficacious for Pi binding.) Polymeric materials having a plurality of cationic sites (e.g., tertiary and quaternary amines) appended thereto constitute the second clinically important class of phosphorus binders.
Phosphorus binding by metal salts is affected by the pH of the solution environment. The solution pH affects both the rate of dissolution of the metal salt and the subsequent binding reaction between the metal ion and phosphate. In general, an acidic pH is best to dissolve and ionize the salt, but reaction of the metal with the phosphate and precipitation of metal phosphate from solution is optimal at higher values of pH.
Of the metal salts listed above, calcium salts constitute the group of phosphate binders used most extensively by patients worldwide to control serum Pi levels (Table 1).
TABLE 1Calcium salts that have been studied as Pi bindersCalcium% Ca,Sourceby weightRemarksCalcium40%Wide variations in ionized Ca bioavailability andCarbonatetrace metal contamination; widely used outsidethe U.S. for Pi bindingCalcium23%Regurgitation of acetic acid (vinegar breath) is aAcetatesignificant side effect. Only calcium acetate hasbeen approved by the U.S. Food and DrugAdministration for clinical use as a phosphatebinder.Calcium21%Enhances absorption of calcium and other metalsCitratefrom the gut, including (adventitious) dietaryaluminum.Calcium31%Chronic absorption of formate is reported to causeFormatealbuminuria and hematuria. Pungent odor.Skin irritant.Calcium14%Used as a dietary supplement, not as a Pi binder.LactateCalcium9%Used as a dietary supplement, not as a Pi binder.Gluconate
In U.S. Pat. No. 4,889,725 Veltman discloses a means for promoting the neutralization reaction between particulate calcium carbonate and ionized phosphate by adding a material formed by the reaction of particulate calcium carbonate and dilute hydrofluoric acid. The products of this invention are useful in lowering serum phosphorus levels in patients undergoing renal dialysis, and are also useful as antacids.
A common treatment for controlling Pi levels is disclosed in U.S. Pat. No. 4,870,105 to Fordtran, which discloses a calcium acetate phosphorus binder for oral administration to an individual for the purpose of inhibiting gastrointestinal absorption of phosphorus. It further discloses a method of inhibiting gastrointestinal absorption of phosphorus, comprising administering orally the calcium acetate phosphorus binder, preferably close in time to food and beverage consumption. Likewise, U.S. Pat. No. 6,576,665 to Dennett, Jr. et al. discloses a composition for inhibiting gastrointestinal absorption of phosphorus in an individual. The composition includes a quantity of calcium acetate sufficient to bind the phosphorus and having a bulk density of between 0.50 kg/L and 0.80 kg/L and is dimensioned to form a caplet for fitting within a capsule. Further provided is a method for administering the calcium acetate composition. Likewise, U.S. Patent Application 2003/0050340 to Dennett, Jr., et al. discloses a composition for binding phosphorus within the gastrointestinal tract of an individual. The composition includes a quantity of calcium acetate having a specific bulk density sufficient to bind the phosphorus in the gastrointestinal tract of an individual. Further provided is a method for administering the calcium acetate composition.
U.S. Pat. No. 4,689,322, to Kulbe et al. provides calcium salts or calcium mixed salts of polymeric, anionic carboxylic acids and/or an ester of sulfuric acid, and methods for their preparation and use, discloses a pharmaceutical product which contains at least a calcium salt or a calcium mixed salt of a natural or chemically modified polymeric, anionic carboxylic acid and/or an ester of sulfuric acid, and additive materials and/or carrier materials. There are further disclosed calcium salts, and methods of preparation thereof, comprised of polymannuronic acid, polygalacturonic acid, polyglucuronic acid, polyguluronic acid, the oxidation products of homoglycans, the oxidation products of heteroglycans, or their mixtures, for controlling the levels of phosphorus, calcium and iron in patients with chronic uremia and/or the control of the oxalate and/or phosphate of the blood in kidney stone prophylaxis.
U.S. Pat. Nos. 6,160,016 and 6,489,361 B1 to DeLuca disclose a calcium formate composition for oral administration to an individual for the purpose of inhibiting gastrointestinal absorption of phosphorus. It further discloses a method of inhibiting gastrointestinal absorption of phosphorus, comprising administering orally the composition, preferably close in time to food and beverage consumption. Further, DeLuca discloses a method of inhibiting gastrointestinal absorption of phosphorus, comprising administering orally the calcium formate composition of his invention, preferably close in time to food and beverage consumption.
U.S. Pat. No. 6,887,897 B2 (Walsdorf et al.) discloses a calcium glutarate supplement and its use for controlling phosphate retention in patients on dialysis and suffering from renal failure and associate hyperphosphatemia. Therapeutic benefit can be realized by administering a calcium glutarate compound orally to a patient to increase available calcium and contact and bind with ingested phosphorus in the patient's digestive tract, and thereby prevent its intestinal absorption.
In U.S. Pat. No. 6,926,912 B1 Roberts et al. disclose a non-aluminum containing mixed metal compound or sulphated metal compound useful as phosphate binders in the treatment of hyperphosphatemia. The mixed metal compounds include a mixed metal hydroxyl carbonate containing magnesium and iron and may have a hydrocalcite structure, preferably a non-aged hydrocalcite structure. The phosphate binders disclosed by Roberts et al. have a phosphate binding capacity of at least 30% by weight, based on test methods described in the specification.
In U.S. Pat. No. 7,517,402 B2 Muhammad discloses a phosphate binder, a composition, and a kit, as well as a process for preparing the binder and composition. The binder is characterized as having calcium silicate sites which are connected the one with the other by alumina-silica phosphate bonds.
Ingestion of each of the conventional calcium-containing phosphate binders listed above causes the subject to experience significant side effects. Ingestion of calcium carbonate, for example, causes side effects that include distaste, nausea, flatulence, and constipation. Similarly, ingestion of calcium acetate causes side effects that include distaste, nausea, regurgitation of acetic acid, and constipation. Ingestion of calcium formate causes side effects that include distaste, nausea, albuminuria, and constipation. Ingestion of mixed metal or sulphated compounds having calcium silicate sites which are connected by alumina-silica bonds causes side effects that include absorption of aluminum from the composition and constipation. Side effects reduce patient compliance with dosage regimens.